Chemical compounds chromone-2-carboxylic acids

ABSTRACT

THERE ARE DDESCRIBED CERTAIN MONO-CHROMONE-2-CARBOXYLIC ACIDS OF FORMULA,   2-(HOOC-),4-(O=),5-R5,6-R6,7-R7,8-R8-4H-CHROMENE HAVING ONE SUBSTITUENT IN THE 5 OR 6 POSITION OR HAVING 2 OR MORE SUBSTITUENTS IN THE 5, 6, 7 OR 8 POSITIONS. THERE ARE ALSO DESCRIBED PROCESSES FOR MAKING THE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS, FOR THE TREATMENT OF ASTHMA, CONTAINING THE COMPOUNDS.

United States Patent 3,786,071 CHEMICAL COMPOUNDS CHROMONE-2- CARBOXYLICACIDS Hugh Cairns, Albert Chambers, and Thomas Brian Lee, Loughborough,England, assignors to Fisons Limited, London, England No Drawing. FiledAug. 16, 1971, Ser. No. 172,214 Claims priority, application GreatBritain, Aug. 25, 1970, 40,777/70; Sept. 15, 1970, 43,984/70; Dec. 11,1970, 58,860/ 70; June 3, 1971, 18,807/71 Int. Cl. C07d 7/34 US. Cl.260-3452 28 Claims ABSTRACT OF THE DISCLOSURE There are describedcertain mono-chromone-Z carboxylic acids of formula,

R O I H R1 CODE R, having one substituent in the or 6 position or having2 or more substituents in the 5, 6, 7 or 8 positions. There are alsodescribed processes for making the compounds and pharmaceuticalcompositions, for the treatment of asthma, containing the compounds.

This invention relates to new compounds, methods for their preparationand compositions containing them.

According to our invention we provide compounds of Formula I,

H R l R \0/C0OH Re in which R represents hydrogen, hydroxy or, -OR' inwhich provided that (i) R does not represent propyl when R representshydroXy-propoxy, represents hydroxy-propoxy, (ii) R does not representethyl when R is but-3-enoxy, (iii) two or three of R R R and R are otherthan hydrogen, save that when l (a) R represents a straight chain alkylor alkenyl group containing from 5 to 7 carbon atoms or a branched chainalkyl or alkenyl group containing [from 6 to 8 carbon atoms, or (b) Rrepresents phenyl,

3,786,071 Patented Jan. 15, 197.4

none, one or two of R R and R are other than hydrogen.

(iv) R and R are both ethyl or are both sec. butyl only when R is nothydrogen,

(v) R, is alkyl containing from 4 to 6 carbon atoms when R is loweralkoxy-lower alkoxy, and

(vi) at least one of R and R contains 2 or more carbon atoms when R ishydrogen or hydroxy,

and pharmaceutically acceptable derivatives thereof.

According to our invention We also provide a process for the productionof a compound of Formula I, or a pharmaceutically acceptable derivativethereof, which comprises,

(a) cyclizing a compound of Formula I,

Rs (H) in which R R R R and the provisos are as defined above, and

A and A represent the pairs of groups (i) COCH COCOR" and -OM, or (ii)-H and -O-C(COOM)-=CHCO0M in which R" represents 0M, or a group which isby drolyzable thereto, M represents hydrogen or an alkali metal, and ifnecessary or desired hydrolyzing the group RI! 9 (b) selectivelyhydrolyzing or oxidizing a compound of Formula III,

a R D n (III) in which R R R R and the provisos are as defined above,and D is a group which is hydrolyzable or oxidizable to a -COOH group,

provided that when D is a group oxidizable to a -COOH group none of R RR and R represent an alkyl group other than a t-butyl group, 7

(c) selectively dehydrogenating a compound of F01- mula IV,

or an ester thereof in which R R R R and the pro visos are as definedabove,

(d). producing a compound of Formula Ia,

n5: 0 l Ru I a J-ooon I 7 or anester thereof in which R4,;Rg and theprovisos are as defined above,

by reacting a corresponding compound of Formula V,

R GOOH v or an ester thereof in which R R and the provisos are asdefined above, R is hydrogen or hydroxy, R is hydrogen, hydroxy,hydroxy-lower-alkoxy, or lower alkoxy substituted by a good leavinggroup, and one of R9 and R is,hyclroxy, hydroxy-lower alkoxy, or

lower alkoxy substituted by a good leaving group, with, when R is ahydroxy group, an appropriate alkylene oxide, or a compound of FormulaXIV,

R' X (XIV) in which R' is as defined above, and X represents a goodleaving group; when Rq is hydroxy lower alkoxy, a lower alkanesubstituted by a good leaving group;

or when R is lower alkoxy substituted by a good leaving p, a loweralkanol, or when Rq is hydroxy, lower alkoxy-lower alkane substituted bya good leaving group;

(e) producing a compound of Formula Ib,

or an ester thereof in which the provisos .are as defined above,

R and R have the same significances as R and R above, save that at leastone of R andR represent a group R and R represents an allyl group or anallyl group substituted by alkyl in the position adjacent to the benzenering, said group containing up to 6 carbon atoms,

by subjected a compound of Formula XII,

COOH

or an ester thereof in which the provisos are as defined above,

R' represents an allyl group or an alkyl substituted allyl groupcontaining up to 6 carbon atoms,

and R and R have the same significance as R and R above, save that atleast one of R and R represents hydrogen,

4 to an elevated temperature,

(f) producing a compound of Formula If by replacing an R group with ahydrogen atom in a compound of Formula XIII,

0 COOH or an ester thereof, in which (XIII) R R and the provisos are asdefined above, and

R represents alkyl, aralkyl or acyl, or

(g) producing a compound of Formula Ig,

COOH

or an ester thereof in which R and the provisos are as defined above,and

R K5 and R have the same significance as R R and R above respectively,save that at least one of R R and R represent alkyl containing from 2 to8 carbon atoms as appropriate,

by hydrogenating a corresponding compound of Formula XV,

O R's or an ester thereof in which R; and the provisos are as definedabove, and

R R and R have the same significance as R R and R' above, save that atleast one of R R and R' represent an alkenyl group containing from 2 to8 carbon atoms as appropriate,

and if necessary or desired hydrolyzing the ester of the compound ofFormula I to a compound of Formula I and/or converting the compound ofFormula I to a pharmaceutically acceptable derivative thereof.

The cyclization of process (a) (i) may be carried out by heating, orunder basic or neutral conditions. It is however preferred to carry outthe cyclization in the presence of an acid, e.g. hydrochloric acid, andin a solvent which is inert under the reaction conditions, e.g. ethanol.The reaction may be carried out at from about 20 to C. The group -COR"is preferably an ester group, e.g. R" may be a lower alkoxy group.

The cyclization of process (a) (ii) may be carried out by treating theappropriate compound of Formula II with a cyclizing agent, for example adehydrating agent such as chlorosulphonic, polyphosphoric or sulphuricacid. The reaction is preferably carried out under anhydrous conditionsand may be carried out at a temperature of from about 0 to 100 C.Alternatively cyclization may be achieved by converting the free carboxygroups of the compound of Formula II to acyl halide groups andsubjecting the resulting acyl halide to an intramolecular Friedel-Craftsreaction.

In process (b) the group D may be, for example an ester, acid halide,amide or a nitrile group, which may be hydrolyzed to a -COOH group. Thehydrolysis may be carried out using conventional techniques, for exampleunder mildly basic conditions, e.g. using sodium carbonate, sodiumbicarbonate, or under acidic conditions, e.g. a mixture of aqueousdioxan and hydrochloric acid, or hydrogen bromide in acetic acid. Thehydrolysis may be carried out at a temperature of from about 25 to 120depending on the compounds used. Alternatively the group D may be analkyl, e.g. a lower alkyl such as methyl, an aralkenyl, e.g. styryl, anacyl, e.g. a lower alkanoyl such as acetyl, or an aldehyde, e.g. formylgroup. The oxidation may be carried out using conventional techniqueswhich do not otherwise modify the molecule, for example an alkyl groupmay be oxidized using selenium dioxide, e.g. under reflux in aqueousdioxan; or chromic acid, e.g. under reflux in aqueous acetic acid.Aralkenyl groups may be oxidized using, for example neutral or alkalinepotassium permanganate in aqueous ethanol, and acyl groups may beoxidized using, for example chromic acid or an aqueous hypochlorite,e.g. sodium hypochlorite. Aldehyde groups may be oxidized using, forexample chromic acid or silver oxide.

In process (c) the dehydrogenation may be carried out by oxidizationusing a mild oxidizing agent, for example selenium dioxide, palladiumblack or chloranil, lead tetraacetate or triphenyl methyl perchlorate.Alternatively the dehydrogenation may be carried out indirectly byhalogenation followed by dehydrohalogenation, e.g. by treatment withN-bromosuccinimide or pyridinium bromide perbrornide to yield the3-bromo derivative which is subsequently dehydrobrominated. The reactionmay be carried out in a solvent which is inert under the reactionconditions, e.g. a halogenated hydrocarbon, xylene, or glacial aceticacid. The reaction may be carried out at an elevated temperature, e.g.from 25 to 150 C.

In process (d) the good leaving group X may be, for example, a halide,e.g. a bromide or iodide, or an alkyl or aryl sulphonate, e.g. a methanesulphonate group. The reaction may be carried out in a solvent which isinert under the reaction conditions, e.g. a lower alkanol, a ketone suchas acetone or isobutylmethyl ketone, or dimethylformamide. The reactionmay also be carried out in the presence of an acid binding agent, e.g.potassium carbonate, and optionally also in the presence of a catalyst,e.g. potassium iodide; suitably the reaction is carried out at atemperature of 25 to 150 C. Alternatively process (d) may be carried outusing the compound of Formula V (or preferably an ester thereof), in theform of a thallium salt of the reactive hydroxy group. When a thalliumsalt is used the reaction may be carried out at an elevated temperatureand the product may be recovered from the reaction mixture by solventextraction.

In process (e) the reaction may be carried out under conditionsconventional for a Claisen rearrangement, e.g. at a temperature of about170 to 250 C. optionally in a high boiling solvent which is inert underthe reaction conditions, e.g. tetrahydronaphthalene or a dialkylaniline.

In process (I) the replacement of the group -R by hydrogen atom may becarried out when R is an alkyl, e.g. a lower alkyl such as ethyl, oraralkyl, e.g. benzyl group by using an acid, e.g. HCl in ethanol,aqueous HBr, or HBr in glacial acetic acid. Where R is an acyl, e.g. alower alkanoyl such as acetyl group the reaction may be carried outunder mild alkaline conditions and Where R is an aralkyl, e.g. a benzylgroup, the reaction may be carried out by hydrogenation. The reactionmay be carried out at an elevated temperature.

In process (g) the hydrogenation may be carried out using catalytichydrogenation, for example using a palladium on charcoal catalyst in asuitable solvent, e.g. ethanol. The reaction may conveniently be carriedout at from about 20 to C., preferably at slightly greater thanatmospheric pressure.

In the processes (c), (d), (e), (f) and (g) the ester may be, forexample a lower alkyl ester.

The compounds of Formula II in which A and A represent the pair ofgroups COCH COC0R" and -OM may be made by reacting: a compound ofFormula VII,

R6 COOH;

Rs in which R R R R M and the provisos are as defined above, with acompound of Formula VIII,

R'CZ-CZR" (VIII) The compound of Formula H in which A and A representthe pair of groups H and O-C(COOM) =CH-COOM may be made by reacting acompound of Formula 1X,

la in which R R R R and the provisos are as defined above,

with a dialkyl acetylene dicarboxylate, in conventional manner, followedit necessary by hydrolysis.

The compounds of Formula III may be made in a manner analogous toprocess (a) (i) using a starting material of Formula X,

R6 0 0 CHIC o D in which R R R R M and D are as defined above.

The compounds of Formula X may be made from known compounds in a manneranalogous to that described above for the preparation of thecorresponding compounds of Formula II.

Alternatively the compounds of .Formula III may, for example in the caseof the acid halide, the amide and the nitrile, be made from compounds ofFormula I using conventional techniques, e.g. reaction of an ester ofthe Compound I with ammonia to produce the amide, followed bydehydration of the amide to form the nitrile.

The compounds of Formula IV may be made by cyclizing a compound ofFormula XI,

R COCH=CHCOOM R1 OM Ra (XI) in which R ,R R R M and the provisos are asdefined above,

by treating the compound of Formula XI with a base in a solvent which isinert under the reaction conditions.

The compounds of Formula XI may be made by reacting a compound ofFormula VII with glyoxalic acid or an ester thereof. Alternatively thecompounds of Formula XI may be made by reacting a compound of Formula IXwith maleic anhydride in a solvent in the presence of a Lewis acid, e.g.A101 and decomposition of the resulting complex with dilute acid.

The compounds of Formula IV may also be made by selective hydrogenationof a corresponding compound of Formula I.

The compounds of Formulae V, XII, XIII and XV may be made from knowncompounds by processes analogous to process (a) above.

The compounds of Formulae VII, VHI, IX and XIV are either known or maybe made from known starting materials using conventional techniques.

The compounds of Formula I and the intermediates therefor may beisolated from their reaction mixtures using conventional techniques.

Pharmaceutically acceptable derivatives of the compounds of Formula Iinclude pharmaceutically acceptable salts, esters and amides of the2-carboxylic acid group. Suitable salts include ammonium, alkali metal(e.g. sodium, potassium and lithium) and alkaline earth metal salts(e.g. calcium or magnesium), and salts with suitable organic bases, e.g.salts with lower alkylamines such as methylamine or ethylamine, withsubstituted lower alkylamines, e.g. hydroxy substituted alkylamines orwith simple monocyclic nitrogen heterocyclic compounds, e.g. piperidineor morpholine. Suitable esters include simple lower alkyl esters, estersderived from alcohols containing basic groups, e.g. di-lower alkyl aminosubstituted alkanols, and acyloxy alkyl esters, e.g. a lower acyl-loweralkyl ester, or a bis-ester derived from a di-hydroxy compound, e.g. adi(hydroxy-lower alkyl) ether. The pharmaceutically acceptable salts ofthe basic esters, e.g. the hydrochloride, may also be used. The estersmay be made by conventional techniques, e.g. esterification,transesterification or reaction of the acid, or a salt thereof, with anappropriate compound containing a good leaving group.

The compounds of Formula I and pharmaceutically acceptable derivativesthereof are useful because they possess pharmacological activity inanimals; in particular they are useful because they inhibit the releaseand/or action of pharmacological mediators which result from the in vivocombination of certain types of antibody and specific antigen e.g. thecombination of reaginic antibody with specific antigen (see Example A).In man, both subjective and objective changes which result from theinhalation of specific antigen by sensitised subjects are inhibited byprior administration of the new compounds. Thus the new compounds areuseful in the treatment of asthma e.g. allergic asthma. The newcompounds are also useful in the treatment of so-called intrinsic asthma(in which no sensitivity to extrinsic antigen can be demonstrated). Thenew compounds are also useful in the treatment of other conditions inwhich antigen-antibody reactions are responsible for disease, forexample, hay fever, urticaria and certain other allergic skin diseases.

For the above mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. How ever, in general, satisfactory results areobtained when the compounds are administered at a dosage of from 0.1 to50 mg. per kg. of animal body weight in the test set out in Example A.For man the indicated total daily dosage is in the range of from about 1mg. to 3,500 mg. which may be administered in divided doses from 1 to 6times a day or in sustained release form. Thus unit dosage formssuitable for administration (by inhalation or oesophageal- 1y) comprisefrom about 0.17 mg. to 600 mg. of the compound admixed with a solid orliquid pharmaceutically acceptable diluent, carrier or adjuvant.

The compounds of Formula I, and pharmaceutically acceptable derivativesthereof (and in particular the salts, e.g. the alkali metal salts,thereof) have the advantage that they are more readily absorbed and aremore active when administered oesophageally than compounds of similarstructure to the compounds of Formula I.

Preferred compounds of Formula I are those in which R is3-methyl-n-butoxy, hydroxy or tetrahydrofurfuryloxy, R is allyl, ethylor propyl, R is hydrogen, allyl or ethyl and R is hydrogen. It isdesirable in compounds of Formula I that R R ,R7 and R together containfrom 4 to 15 carbon atoms.

According to a specific feature of our invention we provide compounds ofFormula Ip,

in which R represents hydrogen, a hydroxy group, a hydroxy propoxygroup, or a 3-methyl-n-butoxy group,

R represents hydrogen or an alkyl or alkenyl group containing from 2 to6 carbon atoms,

R represents hydrogen or a lower alkoxy-lower alkoxy R representshydrogen or an alkyl or alkenyl group (other than an n-propyl group)containing from 2 to 6 carbon atoms, R representing an alkenyl groupwhen R represents a hydroxy propoxy group,

two or three of R R R and R are other than hydrogen, save when Rrepresents a 3-methyl-n-butoxy group, and provisos (iv), (v) and (vi)are as defined with respect to compounds of Formula I.

According to another specific feature of our invention we providecompounds of Formula Iq,

in which R represents hydrogen, a hydroxy, a hydroxy-propoxy, a branchedchain alkoxy group containing from 6 to 8 carbon atoms, or atetrahydrofurfuryloxy group,

R represents hydrogen or an alkyl or alkenyl group containing from 2 to6 carbon atoms,

R represents hydrogen or a lower alkoxy-lower alkoxy R representshydrogen or an alkyl or alkenyl group containing from 2 to 6 carbonatoms, R representing an 9 alkenyl group when R represents ahydroxy-propoxy group,

two or three of R R Rq and R are other than hydrogen, save the when Rrepresents a branched chain alkoxy group containing from 6 to 8 carbonatoms, one, two or three of R R Rq and R may be other than hydrogen, and

R and R are both ethyl only when R is hydroxy, and provisos (iii), (iv),(v) and (vi) are as defined with respect to compounds of Formula I.

According to yet another specific feature of our invention we providecompounds of Formula Ir,

COOH in which R represents hydrogen, hydroxy or, -OR in which R containsfrom 3 to 8 carbon atoms inclusive, and is a straight or branchedsaturated, or ethylenically unsaturated, hydrocarbon group which groupis optionally substituted by an --OH or by a 5 or 6 membered oxygencontaining heterocyclic ring,

R represents hydrogen, alkyl containing from 1 to 6 carbon atomsinclusive, or alkenyl containing from 2 to 6 carbon atoms inclusive,

R represents hydrogen or lower alkoxy-lower alkoxy,

R represents hydrogen, alkyl containing from 1 to 6 carbon atomsinclusive, or alkenyl containing from 2 to 6 carbon atoms inclusive,

provided that (i) R represents alkenyl when R representshydroxy-propoxy,

(ii) R does not represent ethyl when R is but-3- enoxy,

(iii) two or three of R 2 R R; and R are other than hydrogen, save thatwhen R represents a straight chain alkyl or alkenyl group containingfrom 5 to 8 carbon atoms or a branched chain alkyl or alkenyl groupcontaining from 6 to 8 carbon atoms, none, one or two of R R r, and Rare other than hydrogen,

(iv) R and R are both ethyl or are both sec. butyl only when Rfi is nothydrogen,

(v) R is alkyl containing from 4 to 6 carbon atoms when R is loweralkoxy-lower alkoxy, and

(vi) at least one of R and R contains 2 or more carbon atoms when R- ishydrogen or hydroxy.

According to the invention there is also provided a process for theproduction of a pharmaceutically acceptable salt of a compound ofFormula I, which comprises treating a compound of Formula Ic,

R5 0 i ll Ru 1 R E in which Compounds capable of converting the group Bto a pharmaceutically acceptable salt of a carboxylic acid group includecompounds, e.g. bases and ion exchange resins, containingpharmaceutically acceptable cations, e.g. sodium, potassium, calcium,ammonium and appropriate nitrogen containing organic cations. In generalwe prefer to form the pharmaceutically acceptable salt by treating thefree acid of Formula I With an appropriate base, e.g. with analkaline-earth or alkali metal hydroxide, carbonate or bicarbonate inaqueous solution or by a metathetical process. When a strongly basiccompound is used care should be taken, e.g. by keeping the temperaturesufficiently low, to ensure that the compound of Formula I is nothydrolyzed or otherwise degraded. The pharmaceutically acceptable saltmay be recovered from the reaction mixture by, for example, solventprecipitation and/ or removal of the solvent by evaporation, e.g. byfreeze drying.

According to our invention We also provide a pharmaceutical compositioncomprising (preferably a minor proportion of) a compound of Formula I,or a pharmaceutically acceptable derivative thereof, in combination Witha pharmaceutically acceptable adjuvant, diluent or carrier. Examples ofsuitable adjuvants, diluents or carriers are: for tablets and drages;lactose, starch, talc or stearic acid; for capsules, tartaric acid orlactose; for suppositories; natural or hardened oils or waxes; forinhalation compositions, coarse lactose. For use in inhalationcompositions the compound of Formula I, or the pharmaceuticallyacceptable derivative thereof, preferably has a particle size of from0.01 to 10 microns. The compositions may also contain suitablepreserving, stabilizing and wetting agents, solubilizers, sweetening andcoloring agents and flavorings. The compositions may, if desired, beformulated in sustained release form. We prefer compositions which aredesigned to be taken oesophageally and to release their contents in thegastrointestinal tract.

The invention is illustrated, but :in no way limited by the followingexamples, in which the parts are by weight, the molecular weights wereobtained using a Perkin- Elmer RMU 6 Mass Spectrometer, the N.M.R.values were determined in deuterated dimethyl sulphoxide unlessotherwise stated, the infra-red spectra were determined for potassiumbromide discs and the temperatures are in EXAMPLE 1 8-allyl-5-Z-hydroxypropoxy) -4-oxo-4H-1-benzopyran-2- carboxylic acid (a)3-allyl-2-hydroxy 6 (2-hydroxypropoxy)acetophenone.A mixture of 5 8parts of 3-allyl-2,6-dihydroxyacetophenone, 22.5 parts of propyleneoxide and 0.25 part of a 40% aqueous solution of benzytrimethylammoniumhydroxide in 70 parts of dioxan was heated in a sealed vessel at C. for20 hours. The mixture was cooled and the vessel was opened. The dioxanwas evaporated off and the residual oil was distilled to give 33 partsof 3-allyl-2-hydroxy 6 (2-hydroxypropoxy) acetophenone, boiling point,l58l68 C./0.5-1.0 mm. Hg, melting point 49-51" C.

Analysis.-F0und (percent): C, 67.1; H, 7.20. C H O requires (percent):C, 67.2; H, 7.20'

(b) 8 allyl-S-(2-hydroxypropoxy)-4-oxo-4I-I-1-benzopyran-Z-carboxylicacid hemihydrate.-A solution of 50 parts of3-allyl-2-hydroxy-6-(Z-hydroxypropoxy)-acetophenone in 75 parts ofdiethyl oxalate was added to a stirred solution of sodium ethoxideprepared from the dissolution of 18.5 parts of sodium in 320 parts ofethanol. The resulting mixture was stirred and heated on a steam- -bathfor 3.5 hours, then most of the ethanol was evaporated ofi and theresidue was diluted with 1000 parts of Water and was washed with ether.The aqueous solution was acidified with concentrated hydrochloric acidthen it was extracted with 3 lots of 250 parts of chloroform.Evaporation of the chloroform extract left a residue, which was heatedunder reflux for 30 minutes with 320 parts of ethanol and parts ofconcentrated hydrochloric acid. The mixture was evaporated and theresidue was agitated With 60 parts of ether to give a solid precipitate,which was filtered off, dissolved in bicarbonate solution andreprecipitated upon acidification. The crude product was dried, thendissolved in a 9/1 ether/petrol (B.P. 4060 C.) mixture from which, bycareful evaporation, there was obtained 7.4 parts of8-allyl-5-(2-hydroxypropoxy)-4 oxo- 4H-1-benzopyran-2-carboxylic acidhemihydrate, melting point 75-80 C.

Analysis-Found (percent): C, 60.9; H, 5.46. C H O /2H O requires(percent): C, 61.3; H, 5.43. Mass spectroscopy-molecular weight-Found:304. C H O requires: 304.

(c) 8 allyl-5-(Z-hydroxypropoxy)-4-ox0-4H-1-benzopyran-Z-carboxylicacid, sodium salt.A solution of 1.7 parts of8-allyl-5-(2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acidhemihydrate and 0.42 parts of sodium bicarbonate in 25 parts of waterwas prepared, filtered and freeze-dried to give 1.8 parts of8-ally1-5-(2- hydroxypropoxy) 4 oxo-4H-l-benzopyran-Z-carboxylic acid,sodium. salt.

EXAMPLE 2 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid (a) 6,8dit butyl 4 oxo 4H 1 benzopyran-2- carboxylic :acid.A mixture of 5 partsof 2,4 di-t-bu-tylphenol, 3.55 parts of acetylene dicarboxylic aciddimethyl ester and four drops of benzyl-trimethylammonium hydroxide wereheated on a steam bath for 20 min. The 2,4 di t butylphenoxyfumaric aciddimethyl ester formed was hydrolyzed by heating with 2.8 parts of sodiumhydroxide in parts by volume of water and 8 parts by volume of methanol.The hydrolysis was complete when one layer was obtained. The methanolwas boiled off and the solution was cooled and acidified withconcentrated hydrochloric acid. The crude 2,4-di-t-butylphenoxyfumaricacid was liberated as an oil, and was extracted into ether. This acidwas purified by extraction with sodium bicarbonate solution which wasWashed well with ether. Acidification of the sodium bicarbonate solutiongave the purified fumaric acid which Was extracted again into ether. Thedried ether extracts were evaporated to give the fumaric acid as an oil.

The di-t-butylphenoxyfumaric acid was cyclized by the cautious additionof 11 parts by volume of chlorosulphonic acid at 5 C. The mixture waskept for min. at room temperature and then poured into water. Theproduct which solidified, was washed well with petroleum ether (B.P.40-60) then crystallized from aqueous ethanol to give 2.8 parts of6,8-di-t-butyl-4-oxo-4H-1-benzopyran- 2-carboxylic acid, melting point230-232 C.

Analysis.Found (percent): C, 71.4; C H O requires (percent): C, 71.5; H,7.33.

(b) 6,8 di t butyl 4 oxo 4H -1- benzopyran 2 carboxylic acid, sodiumsalt.To 5.5. parts of 6,8 di t butyl 4 0x0 4H 1 benzopyran-Z- carboxylicacid was added 1.4 parts of sodium bicarbonate in 150 parts by volume ofwater. The mixture was gently heated on a steam bath until nearly allthe acid had dissolved. The neutral solution was filtered andfreeze-dried to give 5 parts of 6,8 di t butyl 4 oxo-4H-1-benzopyran 2carboxylic acid, sodium salt.

EXAMPLE 3 (a) 6,8-di-tert-butyl-4-oxo-4H-l-benzopyran-Z- carboxylicacid, piperidine salt A solution of 5.0 parts of6,8-di-tert-butyl-4-oxo-4H-1- lbenzopyran-Z-carboxylic acid in 1.7 partsof piperidine and 50 parts of water was filtered and freeze-dried. Theresultant pale yellow powder was washed with hot petroleum ether (B.P.6080 C.), giving 5.6 parts of6,8-di-tert-butyl-4-oxo-4H-1-benzopyran-2-carboxy1ic acid,

pi'peridine salt as a colorless powder, melting point 191- 194 C.(decomposition).

Analysis.Found (percent): C, 71.5; H, 8.65; N, 3.57. C H NO requires(percent): C, 71.29; H, 8.58; N, 3.61.

Spectral confirmation.NMR showed the 3-proton of the benzopyran ring asa singlet at 3.231, and broad signals at 7.051- and 8.607 were assignedto the piperidine ring protons (solvent: deuterium oxide).

(b) 6,8 di-tert-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid,ethylamine salt 5.0 parts of 6,8-di-tert-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid were added to a mixture of 1.5 parts of 70% aqueousethylamine and 50 parts of water. The resultant pale yellow solution wasfiltered and freeze-dried, and the resulting solid was washed with etherto aiford 5.3 parts of 6,8-di-tert-butyl-4-oxo-4H-1 benzopyran2-carboxylic acid, ethylamine salt as a colorless powder, melting point205-206 C. (decomposition).

Analysis-Found (percent): C, 69.2; H, 8.72; N, 3.74. C H NO requires(percent): C, 69.13; H, 8.41; N, 4.03.

Spectral confirmation-The 3-proton of the benzopyran ring gave an NMRsinglet at 3.207, and the N-ethyl group gave a quartet at 7.001- and atriplet at ca. 8.801- (Solvent: deuterium oxide).

EXAMPLE 4 6-allyl-5-hydroxy-4-oxo-4H- l -benzopyran-2-carboxylic acid(a) 2-allyloxy-6-hydroxyacetophenone.A mixture of 15.2 parts of2,6-dihydroxyacetophenone, 12.1 parts of allyl bromide and 13.8 parts ofpotassium carbonate in 100 parts of acetone was stirred and refluxed for7 hours. The acetone was evaporated and water, dilute hydrochloric acidand ether were added.

The ethereal layer was separated, dried and evaporated to leave a yellowoil. This oil was distilled and the fraction boiling at 128-132 C. at0.15 mms. of mercury was collected. This oil solidified on cooling butthin layer chromatography showed it to be a mixture of product andstarting material. The mixture was chromatographed on alumina usingether as eluent. Evaporation of the ether gave a yellow solid whichcrystallized from petroleum ether (B.P. 4060 C.) to give 10.0 parts of2-allyloxy-6- hydroxyacetophenone as yellow needles, melting point45.546.5 C.

Analysis.Found (percent): C, 68.4; H, 5.95. C H O requires (percent): C,68.73; H, 6.29.

(b) 5-allyloxy-4-oxo-4H-1 benzopyran-Z carboxylic acid ethyl ester.To astirred solution of 1.2 parts of sodium in 35 parts of ethanol was addeda solution of 3.85 parts of 2-allyloxy-6-hydroxyacetophenone and 10parts of diethyl oxalate in 50 parts of diethyl ether. The mixture wasstirred and refluxed for 5 hours, then poured into 500 parts of diethylether.

The product was then extracted into water (3X 120 ml.) and the aqueoussolution was acidified with concentrated hydrochloric acid and extractedinto chloroform (3X ml.). The chloroform solution was dried over sodiumsulphate and evaporated to leave a red oil. This oil was dissolved in 30parts of ethanol, a few drops of concentrated hydrochloric acid wereadded and the solution was refluxed for 5 minutes. On cooling, 2.7 partsof a solid crystallized out, melting point 97 C. which was shown to be amixture of acid and ester by thin layer chromatography. This solid waswashed with aqueous sodium bicarbonate solution and filtered to leave2.5 parts of 5-allyloxy-4-oxo-4H-1 benzopyran-Z-carboxylic acid ethylester, melting point 122123 C. which was one spot on a thin layerchromatogram.

Analysis.Found (percent): C, 65.5; H, 5.10. C H O requires (percent): C,65.7; H, 5.15.

(c) 6 allyl 5-hydroxy-4-oxo-4H-l-benzopyran-Z-carboxylic acid ethylester.3.44 parts of 5-a1lyloxy-4-oxo 13 4H-1-benzopyran-2-carboxylicacid ethyl ester was heated at 200 C. for 1% hours. On cooling, the masssolidified and was then dissolved in ether and chromotographed onalumina using ether as eluent. The ethereal solution was concentratedwhence 2.5 parts of 6-allyl-5-hydroxy-4-oxo-4H-l-benzopyran-2-carboxylic acid ethyl ester crystallized as yellowplates, melting point 99-100 C.

Analysis.Found (percent): C, 65.5; H, 5.25. C H O requires (percent): C,65.69; H, 5.15.

(d) 6 allyl 5-hydroxy-4-oxo-4H-l-benzopyran-Z-carboxylic acid.-Asuspension of 2.0 parts of6-allyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester inaqueous sodium bicarbonate solution Was stirred and heated at 100 C.till solution was complete. The solution was treated with charcoal,filtered and acidified with dilute hydrochloric acid to give a yellowprecipitate. This solid was crystallized from ethanol to give 0.84 partof 6-allyl- 5-hydroxy-4-oxo-4H-1-benzopyran-2 carboxylic acid as yellowneedles, melting point 222-224 C.

Analysis.-Found (percent): C, 63.7; H, 4.16. C H O requires (percent):C, 63.4; H, 4.09.

(e) 6 allyl 5-hydroxy-4-oxo-4H-1=benzopyran-2-carboxylic acid sodiumsalt-A solution of 0.7 part of 6- allyl5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid and 0.24 part ofsodium bicarbonate in 50 parts of water was freeze-dried to give 0.7part of 6-allyl-5-hydroxy-4- oxo-4H-l-benzopyran-2-carboxylic acidsodium salt as a yellow solid.

EXAMPLE 5 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid (a)3,5-di-t-butyl-Z-hydroxyacetophenone.--A mixture of 20.6 parts of2,4-di-t-butylphenol, 19.2 parts of acetic anhydride and 80 parts ofboron trifluoride: acetic acid complex was heated for 2 hours at 100 C.After pouring into ice cold dilute hydrochloric acid the mixture wasextracted with ether which was washed with water, sodium hydrogencarbonate solution and Water. Addition of 40% sodium hydroxide solutioncaused the precipitation of sodium 2,4-di-t-butylphenate. The ether wasdecanted, washed with water, dried over magnesium sulphate andevaporated to a-brown oil. Distillation under reduced pressure gave apale yellow liquid: b. 100 C which crystallized to give a compound, M.P.4546 C Analysis.Found (percent): C, 77.7; H, C H O requires (percent):C, 77.37; H, 9.74.

(b) 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid ethyl ester.Asolution of sodium ethoxide, prepared from 0.46 part of sodium and 25parts of ethanol, was added with stirring to a mixture of 1.24 parts of3,5-di-t-butyl-2-hydroxyacetophenone and 1.35 parts of diethyl oxalatedissolved in 50 parts of diethyl ether. The mixture was stirred atreflux for two hours, poured into dilute hydrochloric acid and extractedwith chloroform. The chloroform was washed with water and evaporated toa red oil. The oil was boiled for minutes with ethanol containing 1.0part of concentrated hydrochloric acid. On cooling, the solutiondeposited crystals which were collected to yield 1.3 parts of6,8-di-t-butyl-4-oxo-4H-lbenzopyran-Z-carboxylic acid ethyl ester, M.P.130- 131.5 C.

Analysis.--Found (percent): C, 73.0; H, C H O requires (percent): C,72.7; H, 7.93.

(c) 6,8-di-t-butyl 4 oxo-4H-1-benzopyran 2 carboxylic acid sodiumsalt.-To a chilled solution of 1.02 parts of6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid ethyl ester in100 parts of ethanol was added 3.1 parts of N sodium hydroxide solution.After the solution had been stirred at room temperature for one hour thesolvent was evaporated and the remaining solid was triturated with etherand filtered to yield 0.93 part of 6,8-di-t-butyl-4-oxo-4H-l-benzopyran2 carboxylic acid sodium salt. T

1 4 EXAMPLE 6 5( S-methyl-n-butoxy) -8-propyl-4-oxo-4H- l benzopyran2-carboxylic acid (a) 8-allyl 5 (3-methyl-n-butoxy)-4-oxo-4H-l-benzopyran-Z-carboxylic acid, ethyl ester.A solution of 53parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-Z-carboxylic acid in750 parts of ethanol containing 2.0 parts of concentrated sulphuric acidwas heated under reflux for 20 hours. The ethanol was removed bydistillation and a solution of the residual oil in chloroform was washedwith aqueous sodium bicarbonate solution and water. After drying, thechloroform solution was evaporated to leave an oil. This oil wasdissolved in diethyl ether. On standing 45 parts of8-allyl-5-(3-methyln-butoxy)-4-oxo 4H 1 benzopyran-Z-carboxylic acid,ethyl ester crystallized as yellow needles, melting point 104-l06 C.

Analysis.Found (percent): C, 69.70; H, 7.22. C H O requires (percent):C, 69.75; H, 7.02.

Spectral confirmation.-Molecular weight=344 by mass spectrometry.

NMR (CDCl solution) showed the ethyl ester protons as a quartet andtriplet at 5.631- and 8.621 respectively.

(b) 5-(3-methyl-n-butoxy) 8 n propyl-4-oxo-4H-1- benzopyran-Z-carboxylicacid.-A suspension of 12.05 parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-Z-carboxylic acid,ethyl ester in 225 parts of ethanol was treated with 0.2 part of 5%palladium/charcoal catalyst and hydrogenated at a pressure of 4atmospheres. After 30 minutes the hydrogen uptake ceased and thereaction mixture was filtered. The volume of the filtrate was reducedand then water was added. On standing 10.2 parts of 5 (3methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1- benzopyran-2-carboxylic acid,ethyl. ester crystallized as yellow needles, melting point 64.5 65" C.This material was stirred with a hot aqueous solution of sodiumbicarbonate containing some ethanol for two hours. The resultingsolution was cooled, washed with diethyl ether and acidified with dilutehydrochloric acid. The yellow precipitate was collected and crystallizedfrom aqueous ethanol to give 7.2 parts of5-(3-methyl-n-butoxy)-8-npropyl-4-oxo-4H-l-benzopyran-Z-carboxylic acidas yellow needles, melting point 166-167 C.

Analysis.Found (percent): C, 67.50; H, 6.97. C H O requires (percent):C, 67.90; H, 6.97.

Spectral confirmation.--Molecular weight==318 by mass spectrometry.

Infra-red showed the acid carbonyl absorption at 1740 cm." and thebenzopyran ring carbonyl absorption at 1 640 cm.-

NMR showed the 3-proton of the benzopyran ring as a singlet at 3.47.

(c) 5-(3-methyl-n-butoxy) 8 n propyl-4-oxo-4H-1- benzopyran-Z-carboxylicacid, sodium salt.-A mixture of 4.77 parts of5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H- l-benzopyran-Z-carboxylicacid and 1.26 parts of sodium bicarbonate was dissolved in parts ofwater. The solution was filtered and freeze-dried. The hygroscopic solidwas crystallized from ethanol to give 3.3 parts of5-(3-methyl-n-butoxy)-8-n-propyl 4 oxo-4H-l-benzo pyran-Z-carboxylicacid, sodium salt as a white solid.

Spectral confirmation.Infra-red showed the carboxylate ion as a broadabsorption about 1620 cmr NMR showed the 3-proton of the benzopyran ringas a singlet at 3.487.

EXAMPLE 7 5-(3-Methyl-n-Butoxy)-8-n-Propyl-4-Oxo-4H-l-Benzopyran-Z-Carboxylic Acid (a)2-hydroxy-4-(3-methyl-n-butoxy)propiophenone A mixture of 116 parts of2,4-dihydroxypropiophenone, 151 parts of isoamyl bromide and parts ofpotassium carbonate in 300 parts of acetone were stirred and heatedunder reflux for 3 days. The reaction mixture was cooled,

filtered and the filtrate was evaporated to dryness in vacuo. Theresulting oil was dissolved in 500 parts of ether and 200 parts of 2 Nhydrochloric acid. The ether solution was washed with 100 parts of 2 Nhydrochloric acid, 6 lots of 50 parts of 5% aqueous sodium hydroxidesolution, water, 2 N hydrochloric acid, water, dried over anhydrousmagnesium sulphate, filtered and evaporated to dryness in vacuo. Theresulting colorless oil rapidly crystallized to give 108 parts of2-hydroxy-4-(2-methyln-butoxy)propiophenone as a white solid, meltingpoint 43.544.0 C.

Analysis.-Found (percent): C, 70.79; H, 8.42. C H O requires (percent):C, 71.16; H, 8.53.

Spectral confirmation-Molecular weight=236 by mass spectrometry.

N.M.R. showed only one hydroxyl proton at 2.551- in carbontetrachloride, characteristic of a hydrogen bonded phenol.

(b) 5-(3-methyl-n-butoxy)-2-propylphenol 100 parts of zinc wool, 10parts of mercuric chloride, 5 parts of concentrated hydrochloric acidand 150 parts of water were shaken together for 5 minutes. The aqueouslayer was decanted and the amalgamated zinc was covered with 150 partsof water and 200 parts of concentrated hydrochloric acid. A solution of47.2 parts of 2-hydroxy- 4-(3-methyl-n-butoxy)propiophenone in 200 partsof dioxan were added and the mixture was heated under reflux overnight.The reaction mixture was filtered, cooled and extracted with 4 lots of100 parts of ether. The latter were combined and washed with 5 lots of500 parts of water, dried over magnesium sulphate, filtered andevaporated to dryness in vacuo to a colorless oil, which solidified togive 43.7 parts of 5-(3-methyl-n-butoxy)-2- propyphenol as a colorlesscrystalline solid, melting point 40.040.5.

A.nalysis.-Found (percent) C, 75.94; H, 9.78. C H O requires (percent):C, 75.63; H, 9.97.

Spectral confirmation.Molecular weight=222 by mass spectrometry.

N.M.R. displayed the presence of the propyl group and the phenolichydroxy proton now appear at 4.05 '7'.

The infra-red spectrum showed an intense broad H str peak at 3420 cm.and two resolved peaks at 1620 and 1595 cm." for the aromatic C=Cstretch. i

(c) -(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H- 1-benzopyran-2-carboxylicacid (i) 22.2 parts of 5-(3-methyl-n-butoxy)-2-propylphenol weredissolved in 14.2 parts of dimethyl acetylene dicarboxylate followed byaddition of 0.25 parts of benzyl trimethylammonium hydroxide. Themixture was heated at 100 C. for 45 minutes, after which 45 parts of 25%aqueous sodium hydroxide solution were added and the heating at 100 C.was continued for a further 2 /2 hours. The resulting homogeneoussolution was cooled and acidified to pH 1 with 20% v./v. sulphuric acid.The yellow precipitate, produced, was extracted with 4 lots of 200 partsof ether and the latter was washed with 2 N sulphuric acid, water, driedover magnesium sulphate, filtered and evaporated to dryness in vacuo.The resulting yellow oil quickly solidified to give 30.9 parts of ayellow solid. Recrystallization from ethyl acetate/petrol (B.P. 6080 C.)afforded 23.9 parts of 1-[2-propyl-5-(3-methyl-nbutoxy) phenoxy]ethylene- 1,2-dicarboxylic acid.

(ii) parts of 1- [2-propyl-5-(3-methyl-n-butoxy) phenoxy]ethylene-1,Z-dicarboxylic acid were dissolved in 92 parts ofconcentrated sulphuric acid and allowed to stand at room temperature for30 minutes. The mixture was filtered through glass wool into stirred icewater and the resulting yellow-brown syrup was extracted with ethylacetate. The latter was washed with 2 N sulphuric acid, water, driedover magnesium sulphate, filtered and evaporated to dryness in vacuo toyield a brown oil, which crystallized from ethyl acetate/petrol (B.P.60-80 C.).

The yellow crystals were collected and dried in vacuo, giving 1.24 partsof 5-(3-methyl-n-butoxy)-8-propyl-4- oxo-4H-1-benzopyran-2-carboxylicacid, melting point 166167 C.

Spectral con-firmation.--This product was shown to be identical to thatprepared in Example 6.

EXAMPLE 8 6,8-di-n-propyl-4-oxo-4H- l-benzopyran-Z- carboxylic acid (a)6,8-di-n-propyl 4-oxo 4H-l-benzopyran-2-carboxylic acid.A solution of6.2 parts of 6,8-diallyl-4- oxo-4H-1-benzopyran-2-carboxylic acid inparts of ethanol was hydrogenated at room temperature for 45 minutes ata pressure of 45 p.s.i. in the presence of 5% palladized charcoal. Thesolution was filtered and evaporated to afford 6.1 parts of6,8-di-npropyl-4-oxo-4H- l-benzopyran-Z-carboxylic acid, melting pointl83-184 C. after recrystallization from a mixture of ethyl acetate andpetroleum ether (B.P. 60-80 C.).

Analysis.Found (percent): C, 70.0; H, 6.75. C H O requires (percent): C,70.05; H, 6.61.

Spectral confirmation.-Molecular weight=274 by mass spectrometry.

IR acid carbonyl absorption occurred at 1725 cm." and benzopyrancarbonyl absorption at 1620 cmf The N.M.R. spectrum contained a singletat 2.71- due to the benzopyran ring 3-proton (solvent:deuterochloroform).

(b) 6,8-di-n-propyl-4-oxo-4H 1 benzopyran-Z-carboxylic acid, sodiumsalt.A mixture of 4.7 parts of6,8-di-n-propyl-4-oxo-4H-1-benzopyran-2-carboxylic acid and 1.37 partsof sodium bicarbonate was dissolved in 50 parts of water. The filteredsolution was freeze-dried to give 4.5 parts of6,8-di-n-propyl-4-oxo-4H-l-benzopyran-2-carboxylic acid, sodium salt.

Spectral confirmation.IR carbonyl occurred at 1620 cmf The N.M.R.spectrum showed a singlet at 337 due to the benzopyran ring 3-proton(solvent: deuterium oxide).

absorption EXAMPLE 9 6,8-Di-t-Butyl-4-OXo-4H-l-Benzopyran-2CarboxylicAcid (a) 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-l-benzopyran-Z- carboxylicacid, ethyl ester A solution of 12.0 parts of 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-Z-carboxylic acid, ethyl ester in parts of ethanol washydrogenated, using Raney nickel as catalyst, until one equivalent ofhydrogen had been absorbed. The catalyst was removed by filtration andthe ethanol was evaporated to give a residue which was chromatographedon silica gel. Careful elution with a 1:1 mixture of chloroform andlight petroleum (B.P. 6080 C.) gave 3.73 parts of6,8-di-t-butyl-2,3-dihydro-4-oxo-4H 1 benzopyran-2-carboxylic acid,ethyl ester, MIP. 6l63 C., as a yellow solid.

Spectral confirmation.Molecular weight=332 by bass spectroscopy. 0 1-1 0requires 332. 1

(b) 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-l-benzopyran-Z- carboxylic acid,ethyl ester (i) 2,4-di-t-butylphenoxyfumaric acid.A mixture of 2060parts of 2,4-di-t-butylphenol, 1040 parts by volume of acetylenedicarboxylic acid dimethyl ester and 10 parts of benzyltrimethylammoniumhydroxide was heated on a steam bath until a rapid exothermic reactionhad occurred. The mixture was cooled to room temperature and ether wasadded. The ether extract was washed with N sodium hydroxide solution,sodium chloride solution and water, then the ether was removed byevaporation. The residue obtained was refluxed for three hours with 5000parts of N sodium hydroxide solution. After cooling the mixture to roomtemperature, the solid which precipitated was removed by filtration.

The filtrate was evaporated under reduced pressure to give a residuewhich was extracted into ether. The stirred ethereal extract wasacidified with concentrated hydrochloric acid, washed with sodiumchloride solution and dried. 5000 parts of benzene were added andsolvent was removed from the mixture by distillation until a headtemperature of 67 C. was obtained. The resulting solution on cooling toroom temperature gave 1429 parts of 2,4-dit-butylphenoxyfumaric acid asa yellow solid, M.P. 188 C. (after recrystallization from benzene).

Analysis.-Found (percent): C, 67.48; H, 7.53.

requires (percent): C, 67.50; H, 7.50.

Spectral confirmation.-Molecular weight=320 by mass spectroscopy.

(ii) 2,4-di-t-butylphenoxysuccinic acid-3400 parts of a 2 /2 sodiumamalgam were added over one hour to a stirred solution of 320 parts of2,4-di-t-butylphenoxyfumaric acid in 2200 parts of N sodium hydroxidesolution. The reaction mixture was stirred for two hours further, thenwater was added to dissolve the white solid which had formed. Thesolution was decanted from the mercury, extracted with chloroform andthe aqueous layer was sparated.

Concentrated hydrochloric acid was added to the stirred aqueous extractuntil the solution was strongly acidic. The precipitated white solid wascollected by filtration washed with water and dried to give 231 parts of2,4-di-tbutylphenoxysuccinic acid, M.P. 177-181 C.

Spectral confirmation.--Molecular weight=322 by mass spectroscopy. C H Orequires 322.

(iii) 6,8-di-t-butyl-Z,3-dihydro-4-oxo-4H-l-benzopyran- 2-carboxylicacid, ethyl ester.-A mixture of 50 parts of2,4-di-t-butylphenoxysuccinic acid and 100 parts of concentratedsulphuric acid was stirred at room temperature for three hours. Theresulting solution was poured into water, excess sodium bicarbonatesolution was added and the baic solution was extracted with ether. Theaqueous extract was acidified with concentrated hydrochloric acid andthe product was extracted into ether. The ether extract yielded aresidue which was esterified by refluxing for three hours with 200 partsof a 3% v./v. solution of ethanol containing concentrated sulphuricacid. After cooling, water was added and the esterified product wasextracted into ether. The ether extract was washed with sodiumbicarbonate solution and water, dried and the ether was removed byevaporation. Chromatography of the resulting residue on silica gel,eluting with a 3:2 mixture of chloroform and light petroleum (B.P. 40-600.), gave 1 part of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-Z-carboxylic acid, ethyl ester as a semi-solid.

Spectral confirmation.-Molecular weight=332 by mass spectroscopy. C H Orequires 332.

(c) 6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid, ethyl esterA mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-l-benzopyran-Z-carboxylic acid, ethyl ester and 1.84 parts ofN-bromosuccinimide was refluxed in 150 parts of carbon tetrachloride forsix hours. The solution was cooled and then washed with water. Thecarbon tetrachloride extract was dried and the solvent was removed byevaporation. The resulting brown residue was crystallized from lightpetroleum (B.P. 40-60 C.) to give 1.69 parts of6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z- carboxylic acid, ethyl ester,M.P. 130131.5 C. The ester was hydrolyzed to the sodium salt using theprocess of Example 5.

18 EXAMPLE 10 6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid,ethyl ester A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-l-benzopyran-2-carboxylic acid, ethyl ester and 3.33 parts ofselenium dioxide was refluxed in 35 parts of xylene for eight hours. Thereaction mixture was cooled, ether was added and the insoluble inorganicproducts were removed by filtration. Evaporation of the volatilecomponents of the filtrate gave a brown residue which crystallized fromlight petroleum (B.P. 40-60 C.) to give 1.54 parts of6,8-di-t-butyl-4-oxo-4H-l-benzopyran- 2-carboxylic acid, ethyl ester,M.P. 130-131.5 C.

EXAMPLE 11 6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid, ethylester A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester and 9.9 parts oflead tetraacetate was refluxed in 30 parts of glacial acetic acid for6.5 hours. A further 9.9 parts of lead tetraacetate were added and thereflux was continued for another 3.25 hours. After cooling, the reactionmixture was extracted with ether. The ether extract was washed withsodium bicarbonate solution and water and was dried. Evaporation of theether gave an oil which was chromatographed on silica gel using a 9:1mixture of toluene and ethanol for elution. This yielded 0.23 part of6,8-di-t-butyl-4-oxo-4H-l-benzopyran 2 carboxylic acid, ethyl ester,M.P. 130-l3l.5 C. (after crystallization from light petroleum (B.P.40-60 C.). This product was shown by spectral means to be the same asthat of Example 10.

EXAMPLE 12 6,8-di-t-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid, ethylester A mixture of 3.32 parts of 6,8-di-t-butyl-2,3-dihydro-4-oxo-4H-l-benzopyran-2-carboxylic acid, ethyl ester, 1.56 parts oftriphenylmethyl perchlorate and 30 parts of acetic anhydride was heatedat C. for thirty minutes. After cooling, the reaction mixture was pouredinto sodium bicarbonate solution and the resulting mixture was washedwith water, dried and the ether was evaporated to give an oil which waschromatographed on silica gel using a 1:1 mixture of chloroform andlight petroleum (B.P. 40-60 C.) for elution. This yielded 0.14 part of6,8-di-t-butyl-4-oxo-4H-l-benzopyran 2 carboxylic acid, ethyl ester,M.P. 131.5 C. (after crystallization from light petroleum (B.P. 4060C.). This product was shown by spectral means to be the same as thatprepared in Example 10.

EXAMPLE 13 6,8-dipropyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid Amixture of 1.0 part of 6,8-dipropyl-4-oxo-4H-l-benzopyran-2-carboxamide,20 parts of glacial acetic acid, and 20 parts of a solution of hydrogenbromide (45% weight/volume) in glacial acetic acid was heated at refluxfor 3 hours, then added to Water and extracted with chloroform.Extraction of the organic layer with saturated sodium bicarbonatesolution, followed by acidification of the bicarbonate layer, afforded0.16 part of 6,8-dipropyl- 4-oxo-4H-l-benzopyran-Z-carboxylic acid,melting point 173-184 C. (decomposition). The melting point, IR spectrumand thin layer chromatographic properties of this material wereidentical with those of the compound prepared in Example 8.

19 EXAMPLE 14 8-al1yl-5- (3-methyl-n-butoxy) -4-0xo-4H-1-benzopyran-2-carboxylic acid To a stirred solution of 5.0 parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-l-benzopyran-Z-carbonyl chloridein 50 parts of dichloroethane was added 10 parts of water. The mixtureWas stirred at 50 C. for one hour then evaporated to dryness. Theresulting solid was washed thoroughly with aqueous sodium bicarbonatesolution. Acidification of the bicarbonate solution with concentratedhydrochloric acid gave a yellow precipitate which was crystallized fromethyl acetate to give 2.6 parts of 8-allyl 5(3'methyln-butoxy)-4-oxo-4H-1-benzopyran- Z-carboxylic acid, M.P.198-199 C.

EXAMPLE 8-allyl-5- (3-methyl-n-butoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid ethylamine salt An aqueous solution containing 5 partsof 8-allyl-5- (3-methyl n butoxy)-4-oxo-4H-l-benzopyran-Z-carboxylicacid and 1.07 parts of ethylamine (70% v./v.) was filtered andfreeze-dried to give 5 parts of 8-allyl-5-(3-methyl-n-butoxy)-4-oxo4H-l-benzopyran 2 carboxylic acid ethylamine salthemihydrate as a pale yellow solid, M.P. 135-137" C.

'Analysis.Found (percent): C, 64.35; H, 7.34; N, 3.48. C2oH27NO50 /2H2Orequires (percent): C, 64.90; H, 7.57; N, 3.79.

EXAMPLE 16 8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-l-benzopyran-2-carboxylic acid piperidine salt EXAMPLE 178-allyl-5-(3-rnethyl-n-butoxy)-4-oxo-4H-l-benzopyran- 2-carboxylic acidcalcium salt To a solution of 4.93 g. of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-l-benzopyran-Z-carboxylic acidsodium salt in 50* parts of water was added a saturated solution of'1.2parts of calcium nitrate in water. The resulting calcium salt} wasfiltered 01f, washed with water and dried to give 5 parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H- 1-benzopyran-2-carboxylic acidcalcium salt monohydrate as a white solid.

Analysis.Found (percent): C, 62.89; H, 5.91. C H 'CaO J-I O requires(percent): C, 62.80; H, 5.82.

EXAMPLE 18 8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid tris-(hydroxymethyl)methylamine salt A solution of 5.66parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acidand 2.16 parts of tris-(hydroxymethyl)methylamine in 50 parts of ethanolwas refluxed for 2 hours. The solution was filtered and evaporated to anoil which was triturated with ether to give 7.1 parts of8-ally1-5-(3-methyl-n-butoxy)-4-oxo- 4H-l-benzopyran-Z-carboxylic acidtris-(hydroxymethyl) methylamine salt hemihydrate as a pale yellowsolid.

20 Analysis.Found (percent): C, 59.52; H, 7.43; N, 3.06. c,,H,,No,./2H,o requires (percent): C, 59.20; H, 7.18; N, 3.14.

EXAMPLE 19 6,8-di-tert-butyl-4-oxo-4H-1-benzopyran-2-carboxylic acid(,6-diethylarnino)ethyl ester hydrochloride A mixture of 10 parts of6,8-di-tert-butyl-4-oxo-4H-lbenzopyran-Z-carboxylic acid sodium salt and8 parts of ([3-diethylamino)ethyl chloride was shaken for 1 hour inbenzene and refluxed for a further 10 hours. After cooling the inorganicsolid was filtered off and the filtrate was evaporated to leave an oilwhich was heated at C. at 15 mm. pressure for 3hours to remove anyremaining (,B-diethylamino)ethyl chloride. The oil was then dissolved indiethyl ether and to this solution Was added ethereal hydrogen chloride.The resulting solid was filtered off and crystallized fromdioxan/diethyl ether togive 7.01 parts of6,8-di-tert-butyl-4-oxo-4H-1-benzopyran-2- carboxylic acid(,B-diethylamino)ethyl ester hydrochloride hemihydrate as a white solid.

Analysis.Found (percent): C, 64.91; H, 8.23; N, 3.09. C H ClNO J/zH Orequires (percent): C, 64.50; H, 8.06; N, 3.14.

The structure was confirmed by nuclear magnetic reso nance and massspectroscopy.

EXAMPLE 20 8-allyl5- (3-methyl-n-butoxy) -4-oxo-4H-1-benzopyran-2-carboxylic acid(;3-diethylamino)ethyl ester hydrochloride A mixture of10.14 parts of8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acidsodium salt and 8.13 parts of (fl-diethylamino)ethyl chloride wasrefluxed in benzene for 10 hours. The inorganic material was thenfiltered oif and the filtrate was evaporated under vacuum to leave anoil. The oil was heated for 3 hours at 110 C. at 15 mm. pressure toremove the last traces of (,B-diethylamino)ethyl chloride. The residualoil was cooled and dissolved in diethyl ether. To this solution wasadded ethereal hydrogen chloride and the resulting solid was filteredoff and crystallized from dioxan-diethyl ether to give 9.8 parts of8-allyl-5-(3-methyl-n-butoxy)- 4-oxo4H-1-benzopyran 2 carboxylic acid(Ii-diethylamino)ethyl ester hydrochloride hemihydrate as a white solid,M.P. C. over a range.

Analysis.-Found (percent): C, 61.67; H, 7.50; N, 3.02. C H ClNO /2H Orequires (percent): C, 61.95; H, 7.60; N, 3.04.

The structure was confirmed by nuclear magnetic resonance and massspectroscopy.

EXAMPLE 21 8-allyl-5-(3-methyl-n-butoxy) -4-oxo-4H-1-benzopyran-Z-carboxylic acid pivaloyloxymethyl ester To a solution of 5.4 parts ofchloromethyl pivalate in 60 parts of dry acetone were added 6 parts of8-a1lyl-5- (3 methyl-n-butoxy)-4-oxo-4H-l-benzopyran-Z-carboxylic acidsodium salt and 0.1 part of sodium iodide. The mixture was refluxed for10 hours, cooled and evaporated to an oil which was dissolved in diethylether. The ethereal solution was filtered and evaporated under vacuum togive an oil which solidified when triturated with petroleum ether (B.P.40-60" C.). The solid was filtered oil and crystallized from petroleumether (B.P. 60- 80 C.) to give 4.5 parts of8-al1yl-5-(3-methyl-n-butoxy)- 4-oxo-4'H-1-benzopyran 2 carboxylic acidpivaloyloxymethyl ester, M.P.- 79-80 C.

Analysis.Found (percent): C, 66.70; 'H, 7.03. C H O requires (percent):C, 67.0; H, 6.98.

The structure was confirmed by nuclear magnetic resonance and massspectroscopy.

21 EXAMPLE 22 Bis- 8-allyl-5- B-methyI-n-butoxy)-4-oxo-4H-1-benzopyran-Z-carboxylic acid] 2-oxapropan-1,3-diyl ester Toa suspension of 3 parts of 8-allyl-5-(3-methyl-n- 22 The N.M.R. spectrumshowed the 3-proton of the benzopyran ring as a singlet at 2,101 and theexchangeable amide protons at 2.201- in trifluoroacetic acid.

The infra-red spectrum displayed peaks at 3070 cm." for the 3-proton('C-H str) and 1715 and 1690 cm.-

butoxy)-4-oxo-4H-1-benz0pyran-2-carboxylic acid sodium 5 for the 4-oxo(C=O str) nd id I h d (0:0 str) salt in 30 parts of dry acetone, wereadded 0.5 part of respectively.

1,1-dichlorodimethyl ether and 0.1 part of sodium iodide. EXAM L 24 Themixture was refluxed for 1 hour, cooled and filtered.

The filtrate was evaporated to an oil which was dissolved The carboxylicacids shown in Table I were produced in chloroform. The chloroformsolution was filtered and from the appropriate starting materials usingthe method evaporated. The resulting oil was triturated with ether to ofthe example number quoted in the table. The sodium give a solid whichwas filtered oil and crystallized from salts of all of these acids wereprepared by the process benzene/ petroleum ether (B.P. 4060 C.) to give1 part of Example 1(c).

TABLE I Elemental analysis found Method of (percent)- preparationMelting point,

Compound example No. C. C H

6,8-d1ethyl-5-hydroxy4-oxo4H-l-benzopyran-2rcarboxylic acid- 1(b), 4(d)219-211 64. 1 5. 36,8-dial1yl-5-hydroxy-4-oxo-4H-l-banzopyran-2-carboxylic acid 174-17566.6 4.86 7-(2ethoxyethcxy)-6-hexyM-oxo-H-l-benzopyran-2-carboxylic acid1(1)) 128-129 66.1 7. 198-ethyl-5-tetrahydrofurfuryloxydoxMH-l-benzopyran-2-carboxylic acid-.-(1b) 220-222 64.0 5.618-allyl-5-tetrahydrofurfuryloxy-i-oxo-iH-l-benzopyran-2-carboxylic acid1(b) 186-187 65. 05 5. 468-ethyl-5-(8-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylic acid-..1(b) 205-207 66.8 6.75B-allyl-5-(3-methyl-n-bntoxy)4-oxo4H-1-benzopyran-2-carboxylic acid 1(b)198-199 68.00 6. 406,8-dlallyl-5-(8-methyl-n-bntoxy)-4-oxo-4H-1-benzopyran-2-carboxylic aci1(1)) 121. 5-123 70. 8 6. 89 6,8 allyl-4-oxo-4H-bbenzopyran-2-carboxylicacid 1(b) 179-182 71.3 5.275-(3-ethyl-n-butoxy)-4-oxoAH-l-benzopyran-Z-carboxylic acid 1(1))155-160 66.35 6.315-(3-ethyl-n-hexyloxy)-4-oxo4H-1-benzopyran2-carboxylic acid 1(b)146-148 67 55 6.86 5-n-hexy1oxy-4-oxo4H-1-benzopyran-2-carboxylic acid1(1)) 156. 5157.5 66.35 6.264-oxo-5-n-pentyloxy-4H-1-benzopyran-Zcarboxylic acid 1(b) 171-172 65.26.016,8-diethyl-5-(3-methyl-n-bntoxy)-4-oxo-4H-1-henzopyran-2-earboxylicacid 100) 182. -183. 5 68. 4 7. 516,8-dlallyl-5tetrahydrofurl'uryloxyA-oxoAH-l-benzopyran-2-carboxylicacid 1(b) 155. 5-156.5 68.1 6.076,8-diethyl-5-tetrahydrofuriuryloxyAoxo-H-l-benzopyran-2-carboxylic acid1(b) 143.5-144.5 66.03 6.556,8-dimethyl-5-(ii-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-carboxylicacid 1(b) 230 66.81 6.62 4-oxo-6-phenyl-4H-1-benzopyran-2-carboxylicacid. 2 253-254 72.3 8.78

of bis[8 allyl-S-(3-methyl-n-butoxy)-4-oxo-4H-l-benzo- EXAMPLEpyran-Z-carboxylic acid] 2-oxapropan-l,3-diyl ester, M.P. 120-l21 C.

Analysis.-Found (percent): C, 67.20; H, 6.1' C H 0 requires (percent):C, 67.6; H, 6.20.

The esters shown in Table H were prepared from the appropriate startingmaterials by the process shown in the table.

TABLE II Elemental analysis found Method of (percent)- preparationMelting point, Compound example No. C. C H

6,8-diethyl-5-hydroxy-4-oxo-4H-l-benzopyran-zcarboxylic acid ethylester. 5(1)) 82-84 66. 09 6. 256,8-d1al1y1-4-oxo-4H-1-henzopyrau2-carboxylic acid ethyl ester 6(a)65-66 72. 59 6. 288-allzl-5-tetrahydrofuriuryloxy-4-oxo-4H-1-benzopyran-2-carboxylic acidethyl 5(b), 6(a) 115. 5-117 67. 08 6. 22

ea er. 8-ally1-5-(3-methyl-n-butoxy)4oxo-4H-1-benzopyran-2-carboxylicacid ethyl 5(b), 6(a) 104-106 69. 7 7. 22

ester.

EXAMPLE 26 The structure was confirmed by nuclear magnetic resonance andmass spectroscopy.

EXAMPLE 23 8-allyl-S-tetrahydrofurfuryloxy-4-oxo-4H-l-benzopyran-2-carboxamide Anhydrous ammonia gas was passed through a stirredsolution of 38.4 parts of 8-allyl-5-tetrahydrofurfurloxy-4-oxo-4I-I-l-benzopyran-Z-carboxylic acid ethyl ester in 600 parts ofanhydrous ethanol at C. for 3 hours. The resulting dark, reddish brownsolution was cooled to 0 C. A white crystalline solid was formed, whichwas collected and dried in vacuo. 24.7 parts of 8-allyl-5-tetrahydrofurfuryloxy-4-oxo-4H-l-benzopytan-Z-carboxamide were obtained, meltingpoint 211.5-213.5 C.

Analysis.-'Found (percent): C, 65.70; H, 5.84; N, 4.25. C H NO requires(percent): C, 65.64; H, 5.82; N, 4.25.

Spectral confirmation.-Molecular weight=329 by mass spectrometry.

The amides, shown in Table III, were prepared from the correspondingethyl esters by the method of Example 23.

The preparation of the acetophenone starting materials for many of thecarboxylic acids. and ethyl esters shown in Tables I and H are eithergiven here in detail or are listed in Table IV.

(a) 3-ethyl-6-tetrahydrofurfuryloxy-2-hydroxyacetophenone and theextract was washed with water, dried and evapo;

rated. Petroleum ether (B.P. 40-60 C.) was added to the residue and'thesolution was decanted from some tarry material. Evaporation of thepetrol solution gave 21 parts of 3 ethyl 6tetrahydrofurfuryloxy-Z-hydroxyacetophenone as an orange oil.

(b) 3,5-diallyl-2-hydroxyacetophenone A mixture of 57.5 parts of2-allyloxy-3-allylacetophenone and 45 parts of N,N-diethylaniline washeated in a sand bath for 4 hours at a temperature of 220 C. Aftercooling, the reaction mixture was added to excess dilute hydrochloricacid and extracted with diethyl ether. The extract was extracted toatford a red oil which on distillation under vacuum gave 54 parts of3,5-diallyl-2- hydroxyacetophenone, boiling point 100-120 C. at 1.2

mm. mercury.

The structure was confirmed by nuclear magnetic resonance and massspectroscopy.

EXAMPLE 29 6,8-di-t-butyl-4-oxo-4H-l-benzopyran-Z-carboxylic acid Asolution of 2.72 parts of 6,8-di-t-butyl-2-methyl-4- oxo-4H-l-benzopyranand 4.44 parts of selenium dioxide in a mixture of 60 parts of water and250 parts by volume of 'dioxan was heated under gentle reflux for 12hours. After cooling, the solution was filtered and the solvents wereevaporated from the filtrate. The residue thus produced was dissolved in250 parts by volume of chloroform and .the'resulting solution wasextracted with 3 portsof 100 parts of a solution containing 5 parts ofsodium bicarbonate in 100 parts of water. The combined aqueous washingswere acidified with concentrated hydrochloric acid to give a solid whichwas crystallized from aqueous ethanol to give 6,8-di-t-butyl-4-oxo-4H 1benzopyran-Z- carboxylic acid, M.P. 230-232 C.-

EXAMPLE 30 6, 8-diethyl-5-hydroxy-4-oxo-4H- l-benzopyran-Z- carboxylicacid (a) 3,5-diethyl-2-hydroxy-6 methoxyacetophenone.- A mixture of 43.2parts of 3,5-diethyl-2,6-dihydroxyaceto phenone, 30 parts of methyliodide, 15.2 parts of anhydrous potassium carbonate and 300 parts ofacetone was refluxed for two days. After-cooling, the reaction mixturewas filtered and the volatile components of the filtrate removed byevaporation. Chromatography of the residue TABLE IV Method ofpreparation Physical characteristics where Compound Example No. measured4-(Z-ethoxyethoxy)-5-hexyl-2-hydroxyacetophenone 27(0.) Pale yellow oil.3,5-diethyl-2,6-dihydroxyacotophenone 5(a) M.P., 7677 C. 3,5-dia11yl-2,6dihydroxyacet0phenone 27(b) M.P., 55 56 C.3-allyl-6-tetrahydroturturyloxy-2-hydroxyaeetophenone 27 (a) Pale yellowoil. 3-ethyl-Z-hydroxy-6-(3-rnethyl-n-butoxy)acetophenone 1(a) Brownoil. 3-allyl-2-hydroxy-6-(3methyl-n-butoxy)acetophenone. 1(a) Yellowoil. 3,5dial1yl-2hydroxy-6-(3-methyl-n-butoxy)acetopheuone. 1(a) B.P.,147-150 C. at 0.7 mm. Hg. 2-(Zethyl-n-butoxy)-6-hydroxyacetophenone 1(a)Brown oil. Z-(Z-ethyl-n-hexyloxy)-6-hydroxyacetophenon 1(a) Yellow 011.2-n-hexyloxy-6-hydroxyacetophenone 1(a)2-hydroxy-6-n-pentyloxyacetophenone 1(a) 7 7;,3,5-diethyl-2-hydroxy-6-(3methyl-n-butoxy)acetophenone 1(a) Yellow oll.3g-diallyl-Z-tetrahydrofurfuryloxy-G-hydroxyaceto- 27 (a) p enone.3,16;dicthyl-2-tetrahydroturfuryloxy-fi-hydr0xyaceto- 27 (a) p enone.2,6-dihydroxy-3,E-dimethylacetophenone (a) M.P., 144-14645 C.6-hydroxy-3,5-dimethyl-2-(3-methyl-n-butoxy)aceto- 1(a) ed 011. I

phenone.

EXAMPLE 28 2-ch1oro-2-dimethyl-aminomethyl propane. The mixture 1 wasrefluxed for hours, cooled and filtered. The filtrate was evaporated toan oil which was dissolved in diethyl ether. The ethereal solution wasfiltered and evaporated to an oil which was then heated at 100 C. for 6hours under vacuum. After dissolving the oil in ether an excess ofethereal hydrogen chloride solution was added. The resulting solidcomprising 4 parts of 8-allyl -5-(3-methyl-n-b.utoxy.)-4-oxo-4H-l-benzopyran 2 carboxylic acid, 2 dimethylaminomethyl prop-2-ylester hydrochloride hydrate was filtered oif, washed with ether andcrystallized from benzene as a white solid M.P. 183184 C.

Analysis.Found (percent): C, 61.75; H, 8.04; N, 2.82. C H ClNO -H Orequires (percent): C, 61.4; H, 7.67; N, 2.98.

obtained on silica gel, eluting with 4: 1 and 2:1 mixtures of lightpetroleum and ether, gave 32 parts of 3,5-diethy1-2-hydroxy-6-methoxyacetophenone as an oil.

Spectral confirmation. Molecular weight=222 by mass spectroscopy. C H O'requires 222.

(b) 6,8-diethyl-5-methoxy-4-oxo-4H 1 benzopyran- 2-carboxylic acid.-Asolution of 13.8 parts of sodium in 300 parts of ethanol was added to astirred solution of 32 parts of 3,5-diethyl-2-hydroxy-6methoxyacetophenone and 99 parts by volume of diethyloxalate in 300parts of ether. The reaction mixture was stirred at room temperature for2 hours and then poured into a stirred mixture of 100 parts ofchloroform, 300 parts of water and 60 parts of concentratedhydrochloric, acid. The chloroform layer was separated and the solventremoved by evaporation to give an oil which was refluxed with a v. /v.solution of ethanol containing concentrated sulphuric acid for fourhours. Evaporation of the ethanol gave .a residue which was refluxedwith ,excess sodium bicarbonate solution for one hour. After cooling,the mixture was acidified with concentrated hydrochloric acid andextracted with chloroform. Evaporation of the chloroform and tritura-,tionof the residue obtained with light petroleum gavepyran-Z-earboxylic acid, M.P. 199-200 C. (after crystallization fromchloroform/ light petroleum).

Analysis-Found (percent): C, 64.4; H, 5.9. C H O requires (percent): C,65.2; H, 5.8.

Spectral confirmation. Molecular weight=276 by mass spectroscopy. C H Orequires 276.

(c) 6,S-diethyl-5-hydroxy-4-oxo-4H-l-benzopyran 2- carboxylic acid.-Amixture of 5 parts of 6,8-diethyl-5- methoxy-4-oxo-4H-l-benzopyran 2carboxylic acid and 130 parts by volume of 48% aqueous hydrobromic acidwas refluxed for seven hours. The reaction mixture was cooled and excesssodium bicarbonate solution Was added. The solution was acidified withconcentrated hydrochloric acid and then extracted with chloroform.Evaporation of the chloroform gave a residue which on trituration withlight petroleum gave 2.3 parts of 6,8-diethyl-5-hydroxy-4-oxo-4Hl-benzopyran-2-carboxylic acid, M.P. 218220 C. (aftercrystallization from ethanol).

Analysis.-Found (percent): C, 63.8; H, 5.6. C H O requires (percent): C,64.1; H, 5.3.

Spectral confirmation. Molecular weight=262 by mass spectroscopy. C H Orequires 262.

EXAMPLE A The procedure set out below may be used to assess theefiectiveness of a compound in inhibiting the release of thepharmacological mediators of anaphylaxis.

In this test, the effectiveness of the compounds in inhibiting thepassive cutaneous anaphylactic reaction in rats is assessed. It has beenproved that this form of test gives reliable qualitative indications ofthe ability of the compounds under test to inhibit antibody-antigenreactions in man.

In this test method Charles River France/Fisons bred rats (male orfemale) having a body Weight of from 100 to 150 gms. are infectedsubcutaneously at weekly intervals with N. brasiliensis larvae in dosesincreasing from about 200 larvae per animal to 12,000 larvae per animalin order to establish the infection. After 8 weeks the rats are bled byheart puncture and 15-20 mls. of blood are collected from each animal.The blood samples are then centrifuged at 3500 r.p.m. for 30 minutes inorder to remove the blood cells from the blood plasma. The serum iscollected and used to provide a serum containing N. brasiliensisantibody. A pilot sensitivity test is carried out to determine the leastquantity of serum required to give a skin weal in control animals in thetest described below of 2 cm. diameter. It has been found that optimumsensitivity of rats in the body weight range 100-120 gms. is obtainedusing a serum diluted with eight parts of physiological saline solution.This diluted solution is called antibody serum A.

The antigen to react with the antibody in serum A is prepared byremoving N. braszliensis worms from the gut of the infested rats,contrifuging the homogenate and collecting the supernatent liquor. Thisliquor is diluted with saline to give a protein content of 1 mg./ml. andis known as solution B.

Charles River France/Fisons bred rats in the body weight range 100 to130 gms. are sensitised by intra dermal injection of 0.1 mls. of serum Ainto the right flank. Sensitivity is allowed to develop for 24 hours andrats are then injected intravenously with 1 ml./100 gms. body weight ofa mixture of solution B (0.25 mls.), Evans Blue dye solution (0.25 mls.)and the solution of the compound under test (0.5 mls. with varyingpercentages of active matter). Insoluble compounds are administered as aseparate intraperitoneal injection 5 minutes before intravenousadministration of solution B and Evans Blue dye. For each percentagelevel of active matter in the solution under test five rats areinjected. Five rats are used as controls in each test. The dosages ofthe compound under test are selected so as to give a range of inhibitionvalues.

Thirty minutes after injection of solution B the rats are killed and theskins are removed and reversed. The intensity of the anaphylacticreaction is assessed by comparing the size of the characteristic blueweal produced by spread of the Evans Blue dye from the sensitizationsite, with the size of the weal in the control animals. The size of theweal is rated as 0 (no weal detected) i.e. inhibition) to 4 (nodifference in size of weal, i.e. no inhibition) and the percentageinhibition for each dose level calculated as:

Percent inhibition (Control group score-treated group score) X 100Contol group score The percentage inhibitions for the various doselevels are plotted graphically for each compound. From these graphs thedosage required to achieve a 50% inhibition of the anaphylactic reaction(ID may be determined.

The compounds are also evaluated in the above manner using intestinaland gastric administration of the compound.

EXAMPLE B Tablet Compound of Formula I, e.g.8-allyl-5-(3-methy1-nbutoxy) 4 oxo 4H 1 benzopyran-Z-carboxylic acid,

Sodium salt mg 500 Binder, e.g. powdered tragacanth percent 1 to 3Lubricant, e.g. magnesium stearate do 0.25 to l Disintegrating agent,e.g. potato starch ..do 5 to 10 Surfactant, e.g. di-octylsodiumsulphosuccinate do 0.25

EXAMPLE C Capsule (hard) Sodium salt of compound of Formula I mg 500Granulating agent, e.g. gum or starch mucilage q.s. Lubricant, e.g.magnesium stearate percent 0.25 to 1 EXAMPLE D Capsule (soft) Sodiumsalt of compound of Formula I mg 500 Polyethylene glycol 400 q.s.

Non-ionic surfactant, e.g. polyoxy ethylene sorbitan mono-oleate, q.s.

R is a straight or branched alkyl or alkenyl group, which group isoptionally substituted by one OH or by one 5 or 6 memberedoxygen-containing heterocyclic ring containing only carbon and oneoxygen in said ring, R together with any substituents thereon containingfrom 3 to 8 carbon atoms inclusive,

R represents hydrogen, alkyl containing from 1 to 6 carbon atomsinclusive, alkenyl containing from 2 to 6 carbon atoms inclusive, orphenyl,

R represents hydrogen or lower alkoxy-loweralkoxy,

27 R represents hydrogen, alkyl containing from 1 to 6 carbon atomsinclusive, or alkenyl containing from 2 to 6 carbon atoms inclusive,

provided that (i) R does not represent propyl when R representshydroxy-propoxy, (ii) R does not represent ethyl when R is but-3-enoxy,(iii) two or three of R R R and R are other than hydrogen, save thatwhen (a) R represents a straight chain alkyl or alkenyl group containingfrom 5 to 7 carbon atoms or a branched chain alkyl or alkenyl groupcontaining from 6 to 8 carbon atoms, or (b) R represents phenyl, none,one or two of R R and R are other than hydrogen, (iv) R and R are bothethyl or are both sec.butyl only when R is not hydrogen, (v) R is alkyl'containing from 4 to 6 carbon atoms when R; is lower alkoxy-loweralkoxy, and (vi) at least one of R and R contains 2 or more carbon atomswhen R is hydrogen or hydroxy.

2. A compound according to claim 1, wherein R is 3-methyl-n-butoxy,hydroxy or tetrahydrofurfuryloxy, R is allyl, ethyl or propyl, R ishydrogen allyl or ethyl and R is hydrogen.

3. A compound according to claim 1, wherein R R R and R together containfrom 4 to 15 carbon atoms.

4. A compound according to claim 1 which is 8-a1lyl- 5 (2hydroxypropoxy) 4 oxo 4H 1 benzopyran- 2-carboxylic acid.

5. A compound according to claim 1 which is6,8-di-tbutyl-4-oxo-4H-1-benzopyran-2-carboxylic acid.

6. A compound according to claim 1 which is 6-ally1-5-hydroxy-4-oXo-4H-l-benzcpyran-2-carboxylic acid.

7. A compound according to claim 1 which is 5-(3- methyl n butoxy) 8 npropyl 4 oxo 4H 1- benzopyran-Z-carboxylic acid.

8. A compound according to claim 1 which is6,8-di-npropyl-4-oxo-4H-1-benzopyran-2-carboxylic acid.

9. A compound according to claim 1 which is 6,8-diethyl 5 hydroxy 4 x04H -,.1 benzopyran 2- carboxylic acid.

10. A compound according to claim 1 which is 6,8- diallyl hydroxy 4 0x04H 1 benzopyran 2- carboxylic acid.

11. A compound according to claim 1 which is 7-(2- ethoxyethoxy) 6 hexyl4 oxo 4H 1 benzopyran- 2-carboxylic acid.

12. A compound according to claim 1 which is 8- ethyl 5tetrahydrofurfuryloxy 4 oxo 4H 1 benzopyran-2-carboxylic acid.

13. A compound according to claim 1 which is S-allyl- 5tetrahydrofurfuryloxy 4 oxo 4H 1 benzopyran- 2-carboxylic acid.

14. A compound according to claim 1 which is 8-ethyl- 5 (3 methyl nbutoxy) 4 0x0 4H 1 benzopyran-Z-carboxylic acid.

15. A compound according to claim 1 which is 8-allyl- 5- 3-methyl-n-butoxy) -4-oxo-4H- 1-benzopyran-Z-carboxylic acid.

16. A compound according to claim 1 which is 6,8- diallyl 5 (3 methyl r1butoxy) 4 0x0 4H 1- benzopyran-2-carboxylic acid.

17. A compound according to claim 1 which is 6,8-diallyl-4-oxo-4H-1-benzopyran-2-carboxylic acid.

18. A compound according to claim 1 which is 5-(3- ethyl n butoxy) 4 oxo4H 1 benzopyran 2- carboxylic acid.

19. A compound according to claim 1 which is 5-(3- ethyl n hexyloxy) 4oxo 4H 1 benzopyran 2- carboxylic acid.

20. A compound according to claim 1 which is 5-11-hexyloXy-4-oxo-4H-l-benzopyran-Z-carboxylic acid.

21. A compound according to claim 1 which is 4-oxo 5 n pentyloxy 4H '1benzopyran 2 carboxylic acid.

22. A compound according to claim 1 which is 6,8- diethyl 5 (3 methyl nbutoxy) 4 oxo 4H 1- benzopyran-Z-carboxylic acid.

23. A compound according to claim 1 which is 6,8- diallyl 5tetrahydrofurfuryloxy 4 -'oxo 4H 1- benzopyran-Z-carboxylic acid.

24. A compound according to claim 1 which is 6,8- diethyl 5tetrahydrofurfuryloxy 4 0x0 4H 1- benzopyran-Z-carboxylic acid.

25. A compound according to claim 1 which is 6,8- dimethyl 5 (3 methyl nbutoxy) l 4 oxo 4H 1- benzopyran-Z-carboxylic acid.

26. A compound according to claim 1 which is 4-oxo-6-phenyl-4H-l-benzopyran-2-carboxylic acid.

27. A compound according to claim 1 wherein the heterocyclic ring is atetrahydrofurfuryl ring.

28. A compound according to claim 1 in the form of a pharmaceuticallyacceptable salt, lower alkyl ester, ester with a di-lower alkylaminesubstituted lower alkanol, bis ester with a di-hydroxyl-lower aIkyDetheror unsubstituted amide thereof.

References Cited UNITED. STATES PATENTS 3,427,324 2/1969 Fitzmaurice260345.2 X 3,629,290 12/1971 Cairns et al. 260-3452 3,652,765 3/1972Ellis et a1. 260-3452 JOHN M. FORD, Primary Examiner US. Cl. X.R. 424283

